Modulation of intracellular lipid access by ATGL determines ferroptosis sensitivity in castration-resistant prostate cancer - Project Summary Prostate cancer (PCa) is the second most common cancer-related mortality cause in American males. Although therapies targeting androgen receptors are generally effective in treating advanced PCa, no curative treatments currently exist for castration-resistant prostate cancer (CRPC). Recent research reveals CRPC’s vulnerabilities to oxidative stress due to its unique metabolic reprogramming. This elevated susceptibility creates an environment favorable for a form of cell death called ferroptosis. Ferroptosis is brought about by the intracellular accumulation of toxic lipid hydroperoxides. Hence, ferroptosis induction represents a promising novel therapeutic approach for drug-resistant cancers. Despite increased sensitivity to ferroptosis, CRPC manages to avert this cellular fate. In this proposal, we have identified a key enzyme involved in lipid metabolism, adipose triglyceride lipase (ATGL), that engenders metastatic castration-resistant prostate cancer cells with the ability to resist ferroptosis. Our preliminary data demonstrates that ATGL facilitates prostate cancer growth, migration, and invasion. In CRPC cell lines, ATGL deletion sensitizes prostate cancer cells to ferroptosis, likely through regulating the GPX4-mediated ferroptotic control pathway. However, the exact mechanism linking ferroptosis and ATGL in CRPC is unknown. Moreover, while ferroptosis inducers (FINs) are hopeful candidates for anticancer agents under development, their use for treatment and how to enhance their efficacy remains underexplored in CRPC. Our central hypothesis is that ATGL promotes the resistance of CRPC to ferroptosis inducers in an oxidizable lipid-dependent manner. Therefore, Aim 1, the F99 phase, is designed to (1) identify the underlying mechanisms by which ATGL modulates the regulatory pathways that lead to ferroptosis, and (2) evaluate the efficacy of a combined therapy employing FINs, ATGL inhibitors, and anti-androgens as well as investigate the underlying mechanisms behind the observed synergy between anti-androgens and ferroptosis inducers in the context of ATGL ablation. Dr. Daniel Frigo, Ph.D., in the Department of Cancer Systems Imaging at MD Anderson Cancer Center is the primary sponsor of this F99 phase. Aim 2, the K00 phase, is to demonstrate the role of ATGL’s transacylation activity and its product, fatty acid esters of hydroxy fatty acid (FAHFA) in prostate cancer. Considering the K00 proposal focuses on metabolism and cancer progression, it will be conducted at a laboratory that excels in these fields. The fulfillment of these aims holds promise to deepen our knowledge of cancer biology and guide the development of innovative complementary therapeutic approaches that enhance the effectiveness of anti- androgens, thus improving the clinical outcomes of patients suffering from advanced prostate cancer. The proposal also contains a training plan that details further scientific, technical, and professional training. The plan is formulated to ensure the successful completion of the project and a smooth transition to a future career as an independent investigator.
